Current antivirals can control but not eliminate hepatitis B virus (HBV) infection, because HBV establishes a stable nuclear cccDNA. Interferon-alpha treatment can clear HBV but is limited by systemic side effects. IFN-alpha is known to exert transcriptional, post-transcriptional and epigenetic antiviral effects on HBV. We study how interferon-alpha; can induce specific degradation of the nuclear viral DNA without hepatotoxicity and propose lymphotoxin-beta-receptor activation as a therapeutic alternative. Interferon-alpha and lymphotoxin-beta-receptor activation up-regulated APOBEC3A and 3B cytidine-deaminases, respectively, in HBV-infected cells, primary hepatocytes and human liver-needle biopsies. HBV-core protein mediated the interaction with nuclear cccDNA resulting in cytidine-deamination, apurinic/apyrimidinic site formation and finally cccDNA degradation that prevented HBV-reactivation. On the other hand, genomic DNA was not affected. Our data indicate that cccDNA degradation is possible and can be induced without side effects on the infected host cell. An important task will be testing of combinations of nucleos(t)ide analogues with novel anti-viral strategies (e.g. LT-beta agonists or adoptive T-cell therapy) to activate A3A or A3B to cure hepatitis B. Thus, inducing nuclear deaminases, e.g., by lymphotoxin-beta-receptor activation allows development of new therapeutics that, combined with existing antivirals may cure hepatitis B. The interplay between intracellular innate immunity and HBV remains poorly understood. Previous clinical and chimpanzee studies showed negligible induction of pro-inflammatory cytokines and interferon-stimulated genes (ISGs) in the acute phase of HBV infection. Yet, recent in vitro studies identified RNA and DNA elements of the virus that can be sensed by various intracellular pattern recognition receptors (PRRs), suggesting the possibility of innate immune detection of HBV. Notably, the retinoic acid-inducible gene-I (RIG-I), a cytosolic PRR, was shown to directly bind HBV pre-genomic RNA (pgRNA) and trigger a selective Type III interferon (IFN) response. We aimed to clarify innate immune sensing of HBV through in vitro modeling of infection. We first illustrated the impact of anti-HBV nucleoside analogs on the HBV life cycle. HBV susceptible HepG2-NTCP cells were infected with cell-culture derived HBV (HBVcc) and treated with entecavir, an approved NA for chronic Heptitis B treatment. IN HBV infected cells, entecavir strongly inhibited viral DNA levels while exhibiting little effect on viral transcription and antigen production. Contrary to Sato et al, HBV infection did not result in any detectable interferon response. Furthermore, transfection of replication-competent HBV plasmids did not induce IFNs or interferon-stimulated genes (ISGs) above the background levels that were detected in the empty vector-transfected cells. To exclude the possibility that HBVcc was not identical to physiologically infectious virus, HBV-infected patient sera of different genotypes were used to infect stem-cell derived hepatocytes and primary human hepatocytes (PHHs). Interestingly, despite successful infection, HBV in all these models did not induce type I IFNs, type III IFNs and downstream ISGs. These findings support the notion of HBV as a stealth virus that adeptly evades or actively inhibits innate immune response.